Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial
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Abstract
Background
Open-label platform trials and a prospective meta-analysis suggest efficacy of anti–interleukin (IL)-6R therapies in hospitalized patients with coronavirus disease 2019 (COVID-19) receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti–IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19.
Methods
In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 received intravenous sarilumab 400 mg or placebo. The phase 3 primary analysis population included patients with critical COVID-19 receiving mechanical ventilation (MV). The primary outcome was proportion of patients with ≥1-point improvement in clinical status from baseline to day 22.
Results
There were 457 and 1365 patients randomized and treated in phases 2 and 3, respectively. In phase 3, patients with critical COVID-19 receiving MV (n = 298; 28.2% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive, not receiving MV) at day 22 was 43.2% for sarilumab and 35.5% for placebo (risk difference, +7.5%; 95% confidence interval [CI], –7.4 to 21.3; P =.3261), a relative risk improvement of 21.7%. In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio for death for sarilumab vs placebo was 0.76 (95% CI, .51 to 1.13) overall and 0.49 (95% CI, .25 to .94) in patients receiving corticosteroids at baseline.
Conclusions
This study did not establish the efficacy of sarilumab in hospitalized patients with severe/critical COVID-19. Post hoc analyses were consistent with other studies that found a benefit of sarilumab in patients receiving corticosteroids.
Clinical Trials Registration
NCT04315298.
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SciScore for 10.1101/2021.05.13.21256973: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The local institutional review board or ethics committee at each study center oversaw trial conduct.
Consent: All patients provided written informed consent before participating in the trial.Sex as a biological variable not detected. Randomization TRIAL DESIGN, PATIENTS, AND TREATMENTS: We conducted an adaptive, phase 2/3, randomized, double-blind, placebo-controlled, multicenter trial (65 sites in total, with 62 enrolling patients; see full list of sites in the Supplementary Appendix). Blinding All outcomes were assessed by the site investigators, who were blinded to treatment assignment and serum IL-6 levels conducted at a central laboratory. Power Analysis not detected. Table 2: Resources
No …
SciScore for 10.1101/2021.05.13.21256973: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The local institutional review board or ethics committee at each study center oversaw trial conduct.
Consent: All patients provided written informed consent before participating in the trial.Sex as a biological variable not detected. Randomization TRIAL DESIGN, PATIENTS, AND TREATMENTS: We conducted an adaptive, phase 2/3, randomized, double-blind, placebo-controlled, multicenter trial (65 sites in total, with 62 enrolling patients; see full list of sites in the Supplementary Appendix). Blinding All outcomes were assessed by the site investigators, who were blinded to treatment assignment and serum IL-6 levels conducted at a central laboratory. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our trial also has several limitations. The phase 3 sample size estimation based on the phase 2 interim data may have led to an underpowered study, which was further impacted by the 2:1 randomization ratio, leading to a small placebo treatment group. The heterogeneity in the critically ill population as seen in clinical trials in acute respiratory distress syndrome not related to Covid-19 highlights the need for large simple trials such as RECOVERY and SOLIDARITY to adequately assess efficacy of therapeutics in the hospitalized Covid-19 population.27, 28 Another limitation is that the 400-mg dose may be sub-therapeutic, as suggested by a reduction in CRP concentration in the first 7 days and a subsequent rebound (Fig. S3) thereafter, with similar findings reported in a separate trial using sarilumab 400 mg.29 Although an 800-mg treatment arm was included late in the trial, the small sample size makes interpretation challenging. Based on results from the RECOVERY and REMAP-CAP trials, IL-6R inhibitors are currently recommended in combination with corticosteroids in certain hospitalized patients.30, 31 Within the REMAP-CAP study, although the point estimates for tocilizumab and sarilumab are similar, the smaller sample size in the sarilumab group and the lack of benefit of sarilumab in multiple small trials leave open the question about whether the benefit demonstrated with tocilizumab in RECOVERY is a class effect.32 The recent addition of tocilizumab and sarilumab into treatm...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04315298 Completed Evaluation of the Efficacy and Safety of Sarilumab in Hospit… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
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